Increased surface-water temperatures and nutrient enrichment are predicted to alter planktonic communities, impacting biodiversity and ecosystem functioning. While short-term mesocosm studies have reported temperature- and nutrient-driven effects, long-term observations from natural systems remain limited. We studied seasonal plankton communities in 10 lakes in central Poland, five warmed by power plant discharge for six decades and ~ 2°C warmer (annual mean) than control lakes. Based on environmental DNA (eDNA) relative read abundance, green algae (Chlorophyta) were up to 15% more abundant in heated lakes, while golden algae (Chrysophyceae) were up to 7% more abundant in control lakes. Heated lakes exhibited higher diversity of diatoms, green algae, golden algae, cercozoans, basidiomycetes, and chytrids, especially in summer. Their plankton assemblages were compositionally distinct and showed reduced seasonal variability. Multiple regression revealed that rising temperature, interacting with elevated nutrients, reduced diversity in many plankton groups. Warming favored heat-adapted taxa, driving compositional shifts. By providing insights into the long-term impacts of anthropogenic warming, this study underscores the importance of integrating temperature-nutrient interactions in predicting ecosystem responses to climate change.

Nanoplastics (NPs) are emerging contaminants that have received worldwide attention due to their threats to human health. Although NPs have been reported to cause adverse effects on animal retinas, their potential effects on the human retina are poorly understood. This study aims to investigate the impact of polystyrene-NPs (PS-NPs) on human neural retina organoids (hNROs), which mimic the early developing neural retina. hNROs were generated and exposed to PS-NPs with diameters of 100, 200, and 500 nm at concentrations of 0.04, 0.1, and 0.25 mg/mL for two weeks. Smaller-sized PS-NPs induced more severe neurotoxicity to hNROs, as evidenced by decreased organoid size, reduced cell proliferation, increased apoptosis, and altered gene expression profiles. All sizes of PS-NPs exerted toxic effects on retinal development by disrupting axon guidance, anatomical structure development, differentiation, and neurogenesis. PS-NPs exhibited concentration-dependent neurotoxicity, with increasing severity at higher concentrations. Compared with early-stage exposure, pre-early-stage exposure to PS-NPs resulted in a more pronounced inhibition in organoid growth and development. Moreover, we investigated the combined neurotoxic effects of PS-NPs and cadmium (one of the most common heavy metals) exposure. Co-exposure was found to enhance the retinal toxicity of PS-NPs. Collectively, this study demonstrates that NP-induced retinal toxicity exhibits size-, dose-, and developmental stage-dependent effects, advancing our understanding of their health risks.

Eukaryotic algae-dominated microbiomes thrive on the Greenland Ice Sheet (GrIS) in harsh environmental conditions, including low temperatures, high light, and low nutrient availability. Chlorophyte algae bloom on snow, while streptophyte algae dominate bare ice surfaces. Empirical data about the cellular mechanisms responsible for their survival in these extreme conditions are scarce. This knowledge gap was addressed by quantifying proteins for both algal taxa from samples on the southern margin of the GrIS. We show that the streptophyte glacier ice algae have a relative enrichment in proteins involved in environmental signaling and nutrient transport, indicative of cellular readiness to dynamically respond to extreme GriS environmental cues, linked, for example, to photoprotection and the rapid update of scarce nutrients. In contrast, the chlorophyte snow algae have a high abundance of proteins linked to lipid and nitrogen metabolisms, providing evidence for the biological processes sustaining the cellular carbon and nitrogen stores necessary for survival in an oligotrophic environment. We also identify proteins in both taxa linked to the synthesis and breakdown of key cellular pigments. Our study gives novel insights into the cellular biology of these algae and their adaptation to extreme environments.

Spiritual healers in contemporary Germany comprise a heterogeneous and growing group, yet little data exists about them. Therefore, one aim of this study was to learn about which biographical aspects and events were important to the process of becoming a healer and which biographical aspects drove clients to consult a healer. The study was based on semi-structured interviews combined with participant observations. All data were recorded digitally, transcribed, entered into the software program MAXQDA and analysed subjected to Content Analysis. In total, 15 healers (nine male, six female) and 16 clients (13 female, three male) were included. According to the healers, a talent for healing can be inborn, inherited or developed through life experiences. Most of the healers experienced a crisis, which prompted their transformation to healers (the wounded healer type). A smaller group became healers mainly out of interest without going through crisis and by focusing on the spiritual attitude itself (the healer by interest type). The basis of healing is seen as a connection to a transcendent reality, which enables an open, loving and empathetic attitude. The experience of crises and illnesses and the importance of spirituality are major biographical similarities between healers and clients. Near-death experiences as an extreme form of crisis were reported from a few healers and clients. The connections between healing talents and crises, including a deepened exploration of near-death experiences and questions regarding inclining towards spirituality could be of interest in further studies.

Although the enzymatic mechanisms of terpene synthases have been extensively characterized through experimental and computational studies, the atomistic details underlying the product release process have remained elusive. In this study, we present the first atomistic simulations of the initial stages of product release in a terpene synthase, using the bacterial diterpene cyclase CotB2 as a model system. CotB2 catalyzes the complex cyclization of geranylgeranyl diphosphate (GGDP) to the tricyclic diterpene cyclooctat-9-en-7-ol in a single active site through an 11-step reaction cascade. Our MD simulations focus on three model systems representing CotB2 with bound GGDP and cyclooctat-9-en-7-ol, the latter in two states—with the diphosphate fully deprotonated (P2O74−) and protonated diphosphate (HP2O73−). Analysis of the MD trajectories clearly shows that product release is initiated by the dislocation of the diphosphate group, which in turn triggers active site opening via coordinated C-terminal motions. Notably, protonation of the diphosphate moiety appears to be the key event that weakens its interactions with the active site and enables product release. These findings provide crucial mechanistic insight into the final phase of terpene biosynthesis and open new avenues for rational enzyme engineering targeting product release.

Enterococcus spp. are commensal bacteria with increasing clinical relevance due to their role in antimicrobial resistance (AMR). This was a cross-sectional study conducted on broiler chickens in the Soroti and Wakiso districts. It assessed the prevalence, species distribution, AMR profiles, and the presence of mutations in the gyrA gene in antibiotic-resistant Enterococci spp. A total of 402 environmental samples were collected, and 75 % (303/402) tested positive for Enterococcus spp. The most frequently isolated species were E. faecalis (33.1 %), followed by E. faecium (21.4 %) and E. lactis (13.4 %). Phenotypic resistance was observed to sulfamethoxazole-trimethoprim (21.2 %), fluoroquinolone (11.9 %), tigecycline (11.8 %), ampicillin (4.1 %), glycopeptides (2.3 %), gentamicin (2.0 %), and linezolid (1.0 %). Resistance to fluoroquinolones, tigecycline, and sulfamethoxazole-trimethoprim was significantly associated with the semi-intensive system (Fisher’s exact p < 0.001). Only 3.3 % of the isolates were multidrug-resistant. Eleven acquired resistance genes were detected, with tetL and tetM showing significant distribution differences between systems. Mutations in gyrA associated with fluoroquinolone resistance were also identified. While overall AMR levels were low, the detection of resistance to critically important antibiotics not approved for use in poultry highlights potential public health risks. These findings underscore the importance of routine AMR surveillance in poultry. It also highlights the need for deeper investigation into its role in AMR transmission and strategic interventions to limit the development of resistance in food animal production.

While the introduction of wheat into early full-scale farming systems of northern China has received much research attention over the past two decades, few studies have looked at when and how the cultivation of barley, which is better adapted to colder climates, spread across East Asia. New radiocarbon (14C) dates obtained from archaeological barley grains together with material evidence suggest that the crop was introduced to Primorye (Russia’s border region with China and North Korea) no later than the 2nd century BCE, although an earlier arrival sometime between the 4th and 3rd centuries BCE seems possible. From Primorye, the crop probably spread further eastward to Hokkaido. The combined archaeological and chronological evidence suggests that barley-cultivating cultural groups may have migrated to southern Primorye from areas to the west or from southern Liaoning/north-western Korea, which rules out a dispersal via the northern Eurasian steppes or the Japanese archipelago. We propose that a combination of cultural and climatic factors was the driving force behind this migration. While we identify the eastward expansion of the Warring State of Yan around 300 BCE as the primary driver that pushed barley-cultivating populations to migrate, it seems possible that long-term cooling and drying less favourable for farming during 1000–300 BCE added to the political unrest at the northern and eastern boundaries of the Chinese Warring States, or may even have amplified their policies of territorial expansion.

Recent empirical results have linked the N400 ERP with predictive language comprehension processes based on statistical learning (SL). However, links between SL abilities and N400 on the level of individual differences have so far been underexplored. The present study tested SL performance in 29 participants using speech segmentation and artificial grammar learning tasks, followed by EEG recordings of their N400 responses to sentences varying in cloze probability (high, intermediate, low). Mixed-effects models revealed that better online SL performance (SL-ON) was associated with larger N400 amplitudes across conditions. Additionally, working memory showed a significant main effect and interacted with SL-ON in modulating N400 amplitude, while cloze probability also had a robust, independent effect on it. These results demonstrate that individual differences in SL abilities contribute to N400 response variability, supporting the view that the semantic operations reflected by the N400 may involve some form of statistical learning as well. Our findings also raise the possibility that SL and CP tap into distinct levels of predictive mechanisms in language comprehension.

Fibrodysplasia ossificans progressiva (FOP) is an ultra-rare genetic disorder caused by mutations in ACVR1, most commonly the R206H variant. These mutations lead to heterotopic ossification (HO) in soft tissues, such as muscles, tendons, and ligaments. While people with FOP appear healthy at birth, they progressively develop HO starting in childhood, resulting in severe disabilities. Heterotopic ossification can be triggered by injuries, flare-ups, or occur spontaneously, and currently, there are limited medical or surgical treatment options available. To address these challenges, we generated a novel inducible Acvr1R206H knock-in mouse model (C57BL/6 background) that accurately replicates both injury- and non-injury-induced (spontaneous) HO. This model was engineered using an inducible CreERT2 system to express the R206H mutation following Cre-mediated recombination. As expected, muscle injury in these mice resulted in the formation of HO via endochondral ossification, a process in which cartilage is converted into bone. When induced by doxycycline administration employing the rt;tetO-Cre system the same Acvr1ARC-R206H floxed allele also led to the development of similar HO upon muscle injury. Furthermore, we developed a protocol to induce non-injury-induced HO in these mice and determined that HO progresses more slowly in the absence of injury. This mouse model holds great potential as a valuable tool to explore cellular processes underlying disease progression and to serve as pre-clinical model to test the efficacy of therapeutic interventions aimed at preventing HO in FOP.

Wildfires strongly alter soil properties, which in turn affect ecosystem recovery over extended periods, though long-term impacts are less certain. This study investigated a 14-year post-fire chronosequence in Chile’s mediterranean and temperate humid forests, revealing ecosystem-specific soil properties and nutrient recovery mechanisms. By analysing sites at successional stages, the chronosequence approach assessed temporal changes and ecosystem recovery, revealing long-term wildfire effects on soil dynamics and nutrients recovery. Wildfires raised soil bulk density to 0.9 g cm−3 in humid temperate and 1.2 g cm−3 in mediterranean ecosystems. Mediterranean soils experienced greater compaction from organic matter loss, soil aggregate destruction, ash-clogged pores, and topsoil erosion. Soil texture shifts were ecosystem-dependent: mediterranean soils increased 10–12 % in clay and silt through ash redistribution and aggregation, while temperate soils saw sand content rise by 0.74 % and 0.32 % yearly at 0–5 and 5–10 cm depths from thermal disaggregation and erosion. Ground vegetation recovers quickly, but physical soil properties like bulk density require over 14 years to return to pre-fire conditions. In humid temperate forests, ash input initially increased soil pH (4.8 to 5.8), reducing acidity, mitigating aluminium toxicity, while increasing nutrient availability. Base cation stocks increased in mediterranean woodlands (e.g., Ca: up to 0.41 Mg ha−1 y−1) due to ash retention, lower leaching, and ash infiltration into subsoil. Nutrient stocks in humid forests recovered slowly (Ca: 0.087–0.13 Mg ha−1 y−1) due to rainfall-driven leaching and low subsoil reserves. Carbon and N losses were restricted to the litter horizon in temperate forests, recovering via fire-resistant tree inputs, whereas mediterranean soils suffered severe C and N depletion from vegetation loss, erosion, and low N fixation. Fire effects and recovery are ecosystem-specific, shaped by landscape, geology, hydrology, and vegetation resilience. Understanding how fire regimes affect soil and nutrient recovery is vital for improving projections in fire-prone regions.

Recent academic and activist critiques raise important points about the ways in which coloniality, migration and racialization are often overlooked in global health research and practice. In particular, these critiques highlight how such structural forces perpetuate inequalities and exclusions, as well as processes of epistemic violence in global health. While agreeing with these critical interventions, this paper argues for a focus on care and the importance that concrete acts and systems of care in postcolonial, migratory and racialized contexts have on the suffering and vulnerability of individuals and communities. Drawing on case studies from multiple different geographic and social contexts, we argue that the perspective of racialization can highlight how multi-layered inequalities in global healthcare are shaped by the intertwined processes of coloniality and migration; thereby explaining the contextual, structural vulnerability of specific groups of people to certain health conditions and their exclusion from adequate healthcare resources. We argue that social scientists and critical global health scholars and practitioners can play a central role in bringing the three strands of research – coloniality, migration and racialization – into conversation to explore their potential for jointly advancing the care and well-being of individuals and communities in different geographical and social contexts.

In quantum metrology, a major application of quantum technologies, the ultimate precision of estimating an unknown parameter is often stated in terms of the Cramér-Rao bound. Yet, the latter fails to completely characterize the distribution of estimates in the nonasymptotic regime. Optimizing metrology protocols with respect to the Cramér-Rao bound can therefore lead to surprisingly poor finite-sample performance. This can be avoided by quantifying the quality of a metrology protocol by the probability of obtaining an estimate with a given accuracy. Using this intrinsically single-shot quantity naturally accommodates the finite-sample regime. We show that the fundamental limits of this figure of merit can be quantified through a multihypothesis testing problem between quantum states. Building on this connection, we derive an analogue of the Cramér-Rao bound that contains explicit corrections relevant to the finite-sample regime. We apply the finite-sample metrology framework to the example task of phase estimation with an ensemble of spin-1/2 particles, giving unambiguous evidence that large quantum Fisher information does not guarantee that a metrology protocol has a good finite-sample performance. Overall, analyzing the probability of success allows the reliable study of quantum metrology in the finite-sample regime and opens up a plethora of new avenues for research at the interface of quantum information theory and quantum metrology.

Representations are a foundational component of any modeling protocol, including on molecules and molecular solids. For tasks that depend on knowledge of both molecular conformation and 3D orientation, such as the modeling of molecular dimers, clusters, or condensed phases, we desire a rotatable representation that is provably complete in the types and positions of atomic nuclei and roto-inversion equivariant with respect to the input point cloud. In this paper, we develop, train, and evaluate a new type of autoencoder, molecular O(3) encoding net (Mo3ENet), for multi-type point clouds, for which we propose a new reconstruction loss, capitalizing on a Gaussian mixture representation of the input and output point clouds. Mo3ENet is end-to-end equivariant, meaning the learned representation can be manipulated on O(3), a practical bonus. An appropriately trained Mo3ENet latent space comprises a universal embedding for scalar, vector, and tensorial molecule property prediction tasks, as well as other downstream tasks incorporating the 3D molecular pose, and we demonstrate its fitness on several such tasks.

Polydimethylsiloxane (PDMS) is widely used in biomedical applications due to its biocompatibility, chemical stability, flexibility, and resistance to degradation in physiological environments. However, its intrinsic inertness limits further (bio)functionalization, and its hydrophobic recovery compromises the longevity of conventional surface modifications. To address these challenges, we developed a nanoprecipitation method for the straightforward colloidal deposition, covalent thermal crosslinking, and surface anchoring of a chemically tunable, biocompatible polyacrylamide with reactive hydroxyl groups, enabling further surface modifications. This polymer incorporates ∼6 % bioinspired catechol units, introduced via an elegant one-pot Kabachnik-Fields reaction, to facilitate thermally induced network formation and enhance adhesion to plasma-activated PDMS. The resulting uniform coatings exhibited tunable dry layer thicknesses up to 44 ± 7 nm and effectively suppressed PDMS chain rearrangement even after steam autoclaving, ensuring long-term stability in aqueous and ambient environments for at least 90 days. The bioactive post-modification potential was demonstrated in a proof-of-concept study by immobilizing the photosensitizer rose bengal at surface concentrations of 20 or 40 μg cm−2. The coating exhibited antimicrobial activity against S. aureus, achieving a 4-log reduction (99.99 %) in colony-forming units after 30 min of irradiation at 554 nm (342 J cm−2), even when bacteria were suspended in liquid, without direct surface contact. In contrast, antimicrobial activity against E. coli was only observed with minimized liquid volume, bringing the motile bacteria into close contact with the surface. This work established a straightforward and versatile strategy for the stable and bioactive functionalization of PDMS surfaces for application in non-invasive surface decontamination.

Metal coordination is ubiquitous in Nature and central in many applications, ranging from nanotechnology to catalysis and environmental chemistry. Complex formation results from the subtle interplay between different thermodynamic, kinetic, and mechanistic contributions, which remain largely elusive to standard experimental methodologies and challenging for typical modeling approaches. Here, considering some prototypical metal complexes between Cd(II) and Ni(II) with various amine ligands, we present a comprehensive atomistic-level description of their chemical equilibrium, complex formation, and ligand exchange dynamics in aqueous solution, providing an excellent agreement with available association constants and formation rates spanning several orders of magnitude. This is achieved through an effective molecular simulation approach that combines finely tuned interatomic potentials with state-of-the-art enhanced sampling and kinetics techniques. Worthy of note, the nature of the chelate effect, a fundamental concept in coordination chemistry, is fully unravelled through the comparative analysis of the ligand binding reactions of monodentate and bidentate ligands in octahedral complexes. Results provide a complete picture illustrating all the concurrent contributions to this phenomenon, such as entropy, dissociation rates, and ligand binding mechanisms, in some cases contradicting previously held beliefs. This study represents a step forward for the in silico design and applications of coordination complex systems.

Many chirality-sensitive light–matter interactions are governed by chiral electron dynamics. Therefore, the development of advanced technologies making use of chiral phenomena would critically benefit from measuring and controlling chiral electron dynamics on their natural attosecond timescales. Such endeavours have so far been hampered by the lack of characterized circularly polarized attosecond pulses, an obstacle that has recently been overcome1,2. Here we introduce chiroptical spectroscopy with attosecond pulses and demonstrate attosecond coherent control over photoelectron circular dichroism (PECD)3,4, as well as the measurement of chiral asymmetries in the forward–backward and angle-resolved photoionization delays of chiral molecules. We show that co-rotating attosecond and near-infrared (IR) pulses can nearly double the PECD and even change its sign compared with single-photon ionization. We demonstrate that chiral photoionization delays depend on both polar and azimuthal angles of photoemission in the light-propagation frame, requiring 3D momentum resolution. We measure forward–backward chiral-sensitive delays of up to 60 as and polar-angle-resolved photoionization delays of up to 240 as, which include an asymmetry of about 60 as originating from chirality in the continuum–continuum transitions. Attosecond chiroptical spectroscopy opens the door to quantitatively understanding and controlling the dynamics of chiral molecules on the electronic timescale.

While quantum key distribution (QKD) based on two-dimensional (qubit) encoding is a mature, field-tested technology, its performance is lacking for many cryptographic applications. High-dimensional encoding for QKD enables increased achievable key rates and robustness as compared to the standard qubit-based systems. However, experimental implementations of such systems are more complicated, expensive, and require careful security analysis as they are less common. In this work, we present a proof-of-principle high-dimensional time-phase BB84 QKD experiment using only one single-photon detector per measurement basis. We employ the temporal Talbot effect to detect QKD symbols in the control basis and show experimentally obtained simplistic key rates for the two-dimensional and four-dimensional cases, including in an urban fiber network. We present a comparison of a simplistic secret key rate obtained from a standard security proof with the one derived from a recently devised proof using a tunable beam splitter to display security issues stemming from asymmetric detection efficiencies in the two bases. Our results contribute to the discussion of the benefits of high-dimensional encoding and highlight the impact of security analysis on the achievable QKD performance.

This article critically interrogates the unequal structures of life-saving inclusion and life-shortening exclusion that underpin modern citizenship regimes. By connecting the coloniality of citizenship framework with critical and reflexive migration studies on the nexus of death, migration, and citizenship, it introduces the concept of the necropolitics of statelessness. Bringing the works of Hannah Arendt, Michel Foucault, Giorgio Agamben, Achille Mbembe, Orlando Patterson, Sylvia Wynter, and Frantz Fanon into dialogue with each other and with the work of Caribbean human rights professionals and activists, the article captures how the racialized and gendered exclusion from national membership produces deadly effects. To illustrate and support this argument, two interconnected case studies from the Caribbean are spotlighted: the 1937 Parsley Massacre, which targeted Haitians and those presumed to be of Haitian descent in the Dominican Republic, and the 2013 La Sentencia ruling, which rendered Dominicans of Haitian descent stateless and disposable. The necropolitics of statelessness is thus conceptualized as an extreme manifestation of the coloniality of citizenship, highlighting how colonial histories of violence and their present-day legacies perpetuate conditions where stateless individuals – whose very humanity is systematically denied – are subject to sovereign death-making power.

Neuromodulators control mood, arousal, and behavior by inducing synaptic plasticity via G-protein-coupled receptors. While long-term presynaptic potentiation requires structural changes, mechanisms enabling potentiation within minutes remain unclear. Using the Drosophila neuromuscular junction, we show that octopamine, the invertebrate analog of norepinephrine, potentiates evoked neurotransmitter release on the timescale of one minute via a G-protein-coupled pathway involving presynaptic OAMB receptors and phospholipase C. This fast potentiation correlates with elevated signals of the release factor Unc13A and the scaffolding protein Bruchpilot. Live, single-molecule imaging of endogenously tagged Unc13 revealed its instantly reduced motility and increased concentration in synaptic nanoclusters with potentiation. Presynaptic knockdown of Unc13A fully blocked fast potentiation. Moreover, deleting its N-terminal localization sequence mislocalized the protein fragment to the cytosol, but still allowed for rapid plasma membrane recruitment by diacylglycerol (DAG) analog phorbol esters and octopamine, implicating a role of more C-terminal domains. A point mutation of endogenous Unc13 in its DAG-binding C1 domain blocked plasticity-induced nanoscopic enrichment and synaptic potentiation. The mutation increased basal neurotransmission but reduced Unc13 levels, revealing a gain of function and potential homeostatic compensation. The mutation also blocked phorbol ester–induced potentiation, decreased the calcium sensitivity of neurotransmission, and caused short-term synaptic depression. Homeostatic potentiation induced by postsynaptic receptor block mirrored octopamine-induced Unc13 recruitment and required presynaptic OAMB receptors, indicating overlapping machinery. Thus, rapid Unc13 immobilization and nanoscale compaction are salient features of fast presynaptic potentiation.

Background

Family climate substantially influences children’s socio-emotional development. We examined mothers’ mental representations of their children and their relationships in three groups of mothers with young children (0–6 years): mothers (1) with a borderline personality disorder (BPD) (2), with a depressive or anxiety disorder but no BPD (AD/D), or (3) without a current mental disorder (CON). We expected both clinical groups to show more negative mental representations – more expressed emotion reflecting a critical attitude toward the child in general, more hostile attributions to child misbehavior in particular, and a less balanced view of the child (i.e., lower narrative coherence) – than CON mothers. We also expected mothers with BPD to have more impaired mental representations than mothers with AD/D.

Methods

Data were collected as part of an intervention study (at the pre-intervention assessment). To assess parental attributions, 172 mothers with BPD, 69 mothers with AD/D, and 96 CON mothers provided responses to vignettes and participated in a five-minute speech sample coded for expressed emotion and narrative coherence.

Results

BPD was associated with more criticism (OR = 3.17 and OR = 3.93) in comparison with CON mothers and mothers with AD/D, and with lower narrative coherence (OR = 5.45) compared with CON mothers but not compared with mothers with AD/D (OR = 1.41). Only narrative coherence remained significantly associated with group membership after education was controlled for. Mothers with BPD also showed more hostile attributions than CON mothers, with the AD/D group in between.

Conclusion

Without controlling for maternal education, critical attitudes toward the child in general were specifically associated with BPD, hostile attributions were less clearly associated, and narrative coherence was transdiagnostically associated with mental disorders in general. Once education was controlled for, disorder-specific associations were no longer observed, while transdiagnostic associations were maintained. Early interventions may specifically aim to decrease levels of criticism, help mothers increase non-hostile attributions of child misbehavior, and support mothers in building more coherent mental representations of their children.

Trial registration

This study was pre-registered at the German Registry of Clinical Studies (DRKS-ID: DRKS00020460).